In the study by Pedersen et al. (30), APP gene-mutant mice subjected to EODF intervention died within 2–3 weeks. These mice experienced severe hypoglycemia on fasting days, leading to death. Further analysis showed significant abnormalities in the hypothalamic–pituitary–adrenal axis regulation of the stress response in APP gene-mutant mice. This abnormality was associated with the accumulation of Aβ in the cerebral cortex, hippocampus, and hypothalamus, making them unable to respond normally to various stressors, including restraint stress and surgery. Zhu et al. (100) subjected PS1 gene-knockin mice to continuous EODF for 3 months and found that the EODF group exhibited enhanced resistance to excitotoxic damage in hippocampal CA1 and CA3 neurons, with fewer lipid peroxidation products (4-hydroxy-2-nonenal) compared to the AL group, suggesting that inhibition of oxidative stress might be a potential mechanism for the neuroprotective effects of EODF. Guo et al. (101) found that adult 3-month-old SD male rats subjected to 3 months of EODF, compared to the normal diet group, retained glucose and glutamate uptake and mitochondrial function after synaptosomes were exposed to Aβ protein damage, with increased stress protein levels, suggesting that EODF may alter synaptic homeostasis and enhance resistance to damage. Contestabile et al. (102) found that 2-month-old male Wistar rats subjected to 6 months of EODF exhibited reduced acetylcholine transferase (ChAT) reduction in the frontal–parietal cortex after basal forebrain injection of amygdalin compared to the AL group, suggesting that EODF may exert partial neuroprotective effects against this damage. Halagappa et al. (103) conducted a study on 3-month-old triple-transgenic AD (3xTgAD) mice and found that EODF may exert neuroprotective effects by resisting the adverse effects of Aβ protein and tau protein on synaptic function. Zhang et al. (104) showed that IF improved cognitive dysfunction, prevented Aβ deposition in the brain, and restored AQP4 polarity in the AD mouse model (APP/PS1 double-transgenic mice). Additionally, IF downregulated the expression of AQP4-M1 and histone deacetylase 3, reduced the AQP4-M1/M23 ratio, and increased miR-130a expression in the cortical region of APP/PS1 mice. Shin et al. (105) suggested that IF could prevent the worsening of cognitive function, energy metabolism, and dyslipidemia induced by estrogen deficiency in Alzheimer’s rats. Liu et al. (106) found that in the AppNL-GF mouse model of AD, IF reduced neuronal network hyperexcitability and improved hippocampal synaptic plasticity defects in a SIRT3-dependent manner. Li et al. (107) subjected 6-month-old male 3xTg-AD and wild-type mice to IF or AL for 3 months. By bilaterally injecting lentiviral vectors carrying siRNA targeting GSK-3β into the hippocampal dentate gyrus region to modulate GSK-3β activity, the study found that IF promoted neuronal differentiation and maturation in the dentate gyrus and improved the known dysfunction in 3xTg-AD mice. These effects could be reversed by siRNA targeting GSK-3β. After IF, the insulin and protein kinase A signaling pathways were inhibited, while the adenosine monophosphate-activated protein kinase and BNDF pathways were activated. Rangan et al. (108) found that long-term fasting-mimicking diet (FMD) cycles reduced hippocampal Aβ load and tau hyperphosphorylation in E4FAD and 3xTg AD mouse models, enhanced neurogenesis, reduced the number of microglia, and decreased the expression of neuroinflammatory genes, including the superoxide-producing NADPH oxidase (Nox2). However, Lazic et al. (109) evaluated the effects of a preventive EODF regimen on the neurodegenerative phenotype of 5XFAD transgenic mice and found a significant increase in inflammation in the cortex of 5XFAD-EODF mice, with increased glial cell reactivity and/or proliferation, along with increased pro-inflammatory cytokines TNF-α, p38 MAPK, and EAAT2, and decreased GAD67, associated with glutamate excitotoxicity, and increased NMDA receptor subunit 2B in the cortex of 5XFAD-EODF mice. This study suggests that EODF regimens may exacerbate Alzheimer’s-like neurodegenerative and neuroinflammatory changes, indicating the need for caution when using dietary restriction during the prodromal stage of such neurodegenerative diseases.

HD is a movement control disorder caused by selective degeneration of striatal neurons. The mitochondrial toxin 3-nitropropionic acid (3NP) is commonly used to create HD animal models. Bruce-Keller et al. (110) found that after several months of EODF, adult SD male rats showed enhanced resistance to 3NP-induced striatal neuronal damage and improved motor function. Guo et al. (101) found that adult 3-month-old SD male rats subjected to 3 months of EODF, compared to the normal diet group, retained glucose and glutamate uptake and mitochondrial function after synaptosomes were exposed to 3NP, with increased stress protein levels, suggesting that EODF may alter synaptic homeostasis and enhance resistance to damage. Duan et al. (111) studied Huntington’s gene-mutant mice and found that EODF slowed disease progression, increased survival rates, improved motor performance, reduced brain atrophy, and decreased huntingtin aggregate formation and caspase activation, normalized glucose regulation, and restored BDNF and chaperone protein levels in the cortex and striatum compared to the AL group. Ehrnhoefer et al. (112) showed that a scheduled feeding paradigm was sufficient to reduce mutant huntingtin levels in YAC128 mice expressing cleavable mutant huntingtin. Wang et al. (113) divided 6-month-old Q175 mice into two groups: AL and TRF. Q175 mice subjected to TRF treatment were fed on a 6 h feeding/18 h fasting schedule. After 3 months of treatment (when the mice reached the early stage of the disease), TRF-treated Q175 mice showed improved motor activity rhythms and sleep–wake cycles. Finally, using NanoString gene expression assays, the expression of several HD-related markers in the striatum of treated mice returned to WT levels. Whittaker et al. (114) also found that the spontaneous activity and sleep behavior rhythms of TRF-treated BACHD mice improved.

PD is a movement disorder caused by the degeneration of dopaminergic neurons in the substantia nigra. Various models are used to study PD, including α-synuclein-mutant mice, the toxin MPTP, striatal injection of the catecholamine neurotoxin 6-hydroxydopamine (6-OHDA), and others (115). Duan et al. (116) subjected 4-month-old male C57Bl/6 mice to either AL or EODF for 3 months, followed by MPTP administration. The results showed that EODF reduced MPTP-induced motor dysfunction and dopaminergic neuron damage in the substantia nigra, increased levels of the stress proteins HSP-70 and GRP-78 in dopaminergic neurons, and exerted neuroprotective effects. In another study, Holmer et al. (117) found that even when EODF was initiated after MPTP administration, beneficial effects still appeared, including decreased extracellular striatal glutamate levels. However, in another study using a 6-OHDA-induced PD rat model, EODF failed to prevent substantia nigra-striatal degeneration (118). Zhou et al. (119) reported that FMD accelerated motor function preservation and reduced dopaminergic neuron loss in the substantia nigra of MPTP-induced PD mice. FMD reduced the number of glial cells and the release of TNF-α and IL-1β in PD mice. Additionally, the study found that FMD treatment altered the composition of gut microbiota in PD mice, including increased abundance of Firmicutes, Bacteroidetes, and Verrucomicrobia, and decreased abundance of Proteobacteria at the phylum level. FMD also modulated changes in short-chain fatty acids (SCFAs) such as propionate and isobutyrate reduction, as well as butyrate and pentanoic acid and other metabolite increases induced by MPTP. Ojha et al. (120) observed that EODF attenuated MPTP-induced loss of dopaminergic neurons and astrocyte activation in the substantia nigra and striatum. Furthermore, EODF reduced MPTP-induced striatal dopamine depletion, increased phosphorylation of PI3K and Akt, and increased phosphorylation of ERK and CREB, further supporting the involvement of neurotrophic factors in the observed neuroprotection.

ALS is a fatal disease characterized by progressive paralysis caused by degeneration of spinal motor neurons. Some ALS cases are caused by mutations in the Cu/Zn superoxide dismutase (SOD) gene. In contrast to the beneficial effects observed in animal models of AD, PD, and HD, Pedersen et al. (121) found that EODF did not show beneficial effects on disease onset or progression in ALS mice with the Cu/Zn SOD gene mutation, and once symptoms appeared, EODF actually accelerated disease progression. This suggests that dietary restriction may not effectively counteract all neurodegenerative diseases involving genetic changes. One possibility is that dietary restriction may produce different effects on gene expression in motor neurons compared to brain neurons. Another possibility is that dietary restriction may indeed induce the expression of neuroprotective proteins in motor neurons, such as growth factors and stress proteins, but the pathogenic pathways involved in Cu/Zn SOD mutations are not affected by dietary restriction. Further studies on the effects of dietary restriction in transgenic ALS mice may help identify the specific molecular conditions under which DR combats neurodegeneration. Charcot–Marie-Tooth type 1A (CMT1A) is the most common hereditary neuromuscular disease involving abnormal expression of peripheral myelin protein 22 (PMP22), a progressive demyelinating disease of the peripheral nervous system. Madorsky et al. (122) subjected 2-month-old Trembler J (TrJ) neuropathic mice to either AL or EODF for 5 months. The EODF group showed significant improvement in motor performance compared to the AL group, with functional benefits associated with increased myelin protein expression, thickened myelin, reduced redundant basement membrane, and reduced abnormal Schwann cell proliferation. The EODF group also showed improved nerve morphology, accompanied by reduced PMP22 aggregation and increased expression of cytosolic chaperones and components of the autophagy/lysosomal pathway.

Razeghi Jahromi et al. (31) induced EAE in C57BL/6 mice using Myelin Oligodendrocyte Glycopeptide (MOG) 35–55, and mice were subjected to EODF after the first clinical symptoms appeared or 30 days after disease induction, for a total of 10 days. The study found that early fasting could reduce EAE severity by improving spinal cord demyelination, inhibiting IFN-γ and TNF-α secretion, and increasing IL-10 production in spleen cells. Choi et al. (123) found that periodic 3-day FMD could effectively improve demyelination and symptoms in a mouse EAE model. These improvements were associated with increased corticosterone levels and regulatory T (Treg) cells, reduced levels of pro-inflammatory cytokines, TH1 and TH17 cells, and antigen-presenting cells (APCs). Additionally, in EAE and cuprizone MS models, FMD promoted oligodendrocyte precursor cell regeneration and axonal remyelination. Cignarella et al. (124) found that IF improved the clinical course and pathology of EAE models by altering gut microbiota. IF increased the abundance of Lactobacillaceae, Bacteroidaceae, and Prevotellaceae, and enhanced antioxidant microbial metabolic pathways. IF also altered T cells in the gut, reducing IL-17-producing T cells and increasing regulatory T cells. Fecal microbiota transplantation from IF mice improved EAE in immune-receptor mice fed a normal diet. Bai et al. (125) induced EAE in C57BL/6 mice by immunizing with Myelin Oligodendrocyte Glycoprotein 35–55 peptide. After 4 weeks of EAE symptoms, mice were subjected to 3 days of modified FMD followed by 4 days of AL, for a total of two cycles. Compared to the control group, FMD mice showed significant reductions in EAE severity, spinal cord immune cell infiltration, and CNS demyelination. FMD also reversed the accumulation of total CD4+ T cells, particularly CNS-accumulating IFN-γ-producing CD4+ T cells, induced by EAE. Additionally, FMD increased cell proliferation rates in the CNS and enhanced the expression of brain-derived neurotrophic factor (BDNF) and remyelination markers. Wang et al. (126) reported that catecholaminergic (CA) neurons in the ventrolateral medulla (VLM) of mice were activated during fasting and demonstrated that the activity of these CA neurons influenced T cell distribution in EAE. Ablation of VLM CA neurons largely reversed fasting-induced T cell redistribution. Activation of these neurons drove T cells to home to the bone marrow via a CXCR4/CXCL12 axis-dependent mechanism, possibly mediated by a neural circuit stimulating corticosterone secretion.

Chen et al. (127) measured acanthosis in IMQ-induced psoriatic mice and assessed their pathological phenotype. The study found that 2 weeks of TRF reduced psoriatic-like lesions, decreased inflammatory cytokines, and alleviated immunosenescence in mice. TRF increased the number of CD4+ Treg cells in skin lesions while reducing the number of Th2 and Th17 cells in the spleen. Additionally, TRF administration led to a reduction in the number of CD4+ senescent T cells in the dermis and spleen, consistent with the reduced expression of senescence-associated genes in splenic CD4+ T cells. Chen et al. (128) found that IF significantly improved IMQ-induced psoriatic-like dermatitis and reduced the number of γδT17 cells and IL-17 production in draining lymph nodes and psoriatic lesions by inhibiting γδT17 cell proliferation and increasing apoptosis. Additionally, IF significantly reduced the number of monocytes in the blood, which was associated with reduced monocytes, macrophages, and dendritic cells in psoriatic skin inflammation. However, in the study by Hong et al. (129), contrary to expectations, IF resulted in higher levels of anti-dsDNA antibodies, immune complex deposition, and glomerular damage in the kidneys compared to the control group. Proteinuria was also aggravated in the IF group. IF increased the abundance of B cells, plasmablasts, and plasma cells in the spleen and lymph nodes, as well as increased autophagy in plasma cells. Chloroquine-induced autophagy inhibition reduced anti-dsDNA antibody secretion by splenocytes in vitro. These findings suggest that IF exacerbates lupus nephritis in MRL/lpr mice by increasing the formation of self-antibody immune complexes.

In recent years, researchers from the International Collaboration on Repair Discoveries at the University of British Columbia, Canada (130–132), applied EODF to treat rats with acute incomplete cervical and thoracic spinal cord injury (SCI), obtaining positive results in behavioral assessments and evaluations of neuroprotective effects through blood β-hydroxybutyrate levels and BDNF levels. However, another study by the team showed (133) that, in contrast to their previous observations in SD rats, EODF did not provide beneficial effects on tissue preservation or improve hindlimb motor function in SCI mice. The research team suggested that this difference might be related to different metabolic responses to intermittent fasting. Yuan et al. (33) found that rats subjected to IF showed significant improvements in behavioral performance and neuronal survival at the spinal cord injury site, with inhibition of endogenous apoptotic pathways and upregulation of autophagy. Wang et al. (134) found that after EODF intervention, differentially expressed genes (DEGs) were enriched and associated with various biological events, including immune-inflammatory responses, cell differentiation, protein modification, neurogenesis, and apoptosis. Specifically, there were significant spatiotemporal differences in DEGs associated with neuroprotection between the EODF and AL intervention groups. These DEGs were primarily concentrated on days 1, 3, and 7 after SCI. The relative abundance of certain genera was significantly associated with DEGs related to neuroprotection in the EODF-SCI group.

Yu et al. (135) subjected 1-month-old adult SD rats to either AL or EODF for 3 months, followed by middle cerebral artery occlusion (MCAO). The results showed that EODF rats had significantly reduced infarct volumes and improved neurological performance. Arumugam et al. (136) found that IF reduced infarct size, lowered mortality from focal ischemic stroke, and improved brain cell resistance to ischemic injury, involving upregulation of various neuroprotective proteins (neurotrophic factors, chaperones, antioxidants) and downregulation of pro-inflammatory factors (TNF, IL-6, and IL-1β). Fann et al. (77) showed that 4 months of daily 16 h fasting reduced the activation of NF-κB and MAPK signaling pathways in the infarcted tissue of mice after ischemia–reperfusion, decreased NLRP1 and NLRP3 inflammasome activity, and lowered IL-1β and IL-18 levels, reducing inflammation and tissue damage. Manzanero et al. (137) used a method similar to Fann et al. and found that pre-modeling IF led to weight loss and reduced circulating leptin levels, increased neurogenesis in the hippocampus and subventricular zone, and after ischemic injury, the infarct volume in the IF group was less than half that of the AL group, preventing the ischemia-induced decrease in circulating leptin levels. Stroke-induced cell proliferation and neurogenesis decreased in the IF group, possibly related to reduced cell death. Varendi et al. (138) studied the neuroprotective effects of short-term pre-operative fasting on a rat model of focal stroke. The study found that pre-operative fasting for 3 days reduced infarct volume in rats with severe focal stroke, and the neuroprotection was associated with the regulation of innate immunity: elevated circulating neutrophil chemokine ligand 1 before ischemia and reduced pro-inflammatory markers (TNF-α and its receptor, as well as downstream intercellular adhesion molecule-1) in the striatum after reperfusion. Jeong et al. (92) found that 2 weeks of IF reduced infarct volume and brain edema, improved neurological deficits, and reduced neuronal loss and apoptosis in MCAO rats. The mechanisms involved included reduced autophagy flux impairment and inhibition of apoptosis. Kim et al. (139) described transcriptional changes in the brain of IF mice and found that the brain transcriptome of AL group mice exhibited strong, sustained upregulation of deleterious genetic pathways under ischemic stroke, but the activation of these pathways was suppressed in the IF 16 h group. Hu et al. (140) found that post-operative IF reduced oxidative stress in the hippocampus of 2VO rats, as evidenced by decreased MDA concentration and reduced mRNA and protein levels of the reactive oxygen-generating enzyme NADPH oxidase 1. IF treatment also maintained GSH levels and SOD activity, as well as the levels of their upstream regulatory enzymes, thereby preserving antioxidant capacity. Additionally, post-operative IF prevented microglial activation and the elevation of sphingosine-1-phosphate receptor 1 and inflammatory cytokines in the hippocampus of 2VO rats. Poh et al. (141) used 14 to 16-week-old male C57BL/6NTac mice to study the effects of 4 months of IF (16 h of daily fasting) on inflammasome-mediated cell death in the cerebellum after chronic cerebral hypoperfusion (CCH). The study showed that IF reduced inflammasome activation and initiated pathways of apoptosis and pyroptosis in cell death. Song et al. (142) subjected rats to either AL or EODF for 3 months, followed by MCAO surgery, and found that IF or caloric restriction mimetics improved ischemic brain injury and microglial activation and enhanced in vivo angiogenesis. Caloric restriction mimetics or SIRT6 overexpression alleviated ischemic and reperfusion-induced brain injury in vitro. SIRT6 deacetylated H3K9ac and H3K56ac in HAPI cells and BMVECs to inhibit TXNIP. Downregulation of SIRT6 reversed the protective effect of caloric restriction mimetics during in vitro brain ischemia/reperfusion. Liu et al. (143) found that long-term IF improved neurogenesis after brain ischemia by promoting angiogenesis through activation of growth differentiation factor 11 (GDF11) signaling, thereby improving neurological function. Additionally, long-term IF stimulated endothelial cell proliferation, promoted local cerebral blood flow, and upregulated total vascular surface area and microvascular branch points through the GDF11/ALK5 pathway. Jeong et al. (144) subjected mice to daily 16 h fasting, with fasting periods occurring either during the dark phase (active-phase intermittent fasting) or the light phase (inactive-phase intermittent fasting). After 6 weeks of the dietary regimen, the mice underwent transient focal cerebral ischemia, and the study found that compared to the AL group, the active-phase intermittent fasting group exhibited better post-stroke motor and cognitive recovery and less infarction. Additionally, protection of dendritic spine density/morphology and increased expression of postsynaptic density protein 95 were observed in active-phase intermittent fasting. Chelluboina et al. (145) studied adult C57BL/6 male mice and found that compared to the AL group, the IF group showed improved motor function recovery, promoted a beneficial gut microbiota phenotype after transient MCAO, and had higher levels of SCFAs in fecal samples. Mersha et al. (146) found that EODF initiated 1 day after modeling promoted motor recovery in mice.

TBI is characterized by structural or functional brain damage caused by external forces, and ferroptosis, a form of programmed cell death, is closely associated with TBI. Studies have shown that IF can effectively reduce lipid peroxidation and mitochondrial dysfunction, thereby alleviating cognitive impairments caused by injury. Yang et al. (49) conducted a study on 8- to 10-week-old C57BL/6 N mice, revealing that IF significantly improved cognitive function in TBI mice and reduced ferroptosis-related cellular damage. Specifically, IF markedly increased the expression of glutathione peroxidase 4 (Gpx4) and heat shock protein 1 (Hspb1), while inhibiting the elevation of ferroptosis-promoting factors such as Nfe2l2, Slc7a11, and Alox8. Additionally, Cao et al. (147) found that a one-month IF regimen, initiated 3 days post-TBI, enhanced the proliferation of hippocampal subgranular zone neural stem cells, increased neuropeptide Y (NPY) expression in the hippocampus, and improved cognitive performance in the Morris water maze test. These results indicate that IF mitigates TBI-induced cognitive deficits by promoting hippocampal neurogenesis through increased NPY expression. These findings provide new insights into the potential of IF as an intervention strategy for TBI.

Bruce-Keller et al. (110) divided 4-week-old adult SD male rats into AL and EODF groups and selected rats at four time points: 2, 4, 8, and 12 weeks after dietary intervention for bilateral dorsal hippocampal injection of kainic acid. The results showed that EODF significantly reduced hippocampal CA3 region neuronal loss, and Morris water maze tests (latency, exploration trials) showed significant differences between the EODF and AL groups, suggesting that 2–3 months of EODF could significantly reduce kainic acid-induced hippocampal damage and visuospatial memory impairment. Duan et al. (148) found that EODF significantly increased brain-derived neurotrophic factor (BDNF) levels in the hippocampus, cerebral cortex, and striatum of mice and reduced kainic acid-induced hippocampal neuronal damage. Contestabile et al. (102) found that 2-month-old male Wistar rats subjected to 6 months of EODF provided sufficient protection to GABAergic neurons in the hippocampus and olfactory-entorhinal cortex from kainic acid-induced degeneration. Sharma et al. (149) subjected 3-month-old male Wistar rats to 3 months of EODF and found that, compared to the AL group, EODF significantly reduced kainic acid-induced neuronal death in the hippocampal CA3 region and regulated the levels of different antioxidants and antioxidant enzymes in different brain regions, increased heat shock protein 70 (HSP70) expression, and counteracted kainic acid excitotoxicity. Youssef et al. (150) evaluated the effects of short-term (7–10 weeks) EODF on adult (6-month-old) SD rats and found that short-term EODF after adulthood had no effect on normal neuronal function (long-term potentiation) but significantly reduced kainic acid excitotoxicity. Hartman et al. (151) tested the anti-epileptic effects of dietary restriction regimens using epilepsy trials and found that the effects of IF varied with the epilepsy trial: IF increased epilepsy activity in the 6 Hz test and the maximal electroshock seizure test, provided no protective effect against pentylenetetrazol-induced epilepsy, but provided protection against kainic acid-induced epilepsy. Their study suggested that the potential anti-epileptic mechanisms of IF and the ketogenic diet might differ. Karimzadeh et al. (152) evaluated the protective effects of EODF on pentylenetetrazol-induced epilepsy rats through behavioral evaluation and histopathological examination and found that EODF reduced the density of black neurons in the hippocampal CA1 and CA3 regions and reduced the number of TUNEL-positive neurons in the hippocampus. These findings support the anti-epileptic and neuroprotective effects of EODF and suggest that the protective effects of EODF are strongest when intervention is initiated before excitotoxic damage occurs. Landgrave-Gómez et al. (153) found that TRF had anti-convulsive effects by prolonging the latency to forelimb clonic seizures, reducing the seizure severity score, and reducing the number of animals reaching status epilepticus. Additionally, TRF induced changes in signaling pathways regulating energy metabolism, including increased AMPK phosphorylation and decreased Akt kinase phosphorylation. TRF also significantly increased the concentration of β-hydroxybutyrate (β-HB), an endogenous inhibitor of histone deacetylases (HDACs). HDAC activity was significantly reduced, and histone 3 (H3) acetylation was increased in hippocampal homogenates from the TRF group. Dolce et al. (154) fed male NIH Swiss mice (3–4 weeks old) four different dietary regimens for 12–13 days and found that ketogenic diet (KD) mice were protected in the 6 Hz seizure test but exhibited more severe seizure scores in the kainic acid test (cohorts I and II), whereas IF mice showed the opposite. The study suggested that KD and IF do not share the same anti-epileptic mechanisms. Karimzadeh et al. (152) found that PF had anti-convulsive and neuroprotective effects in epileptic rats but emphasized that different PF regimens might have different effects. PF showed the strongest anti-convulsive effect when initiated before excitotoxic damage occurred. Armstrong et al. (155) studied the anti-convulsive effects of TRF in the 6 Hz mouse model. The study found that continuous 8 h TRF and 8hTRF plus weekend ad libitum feeding regimens temporarily increased seizure thresholds in the 6 Hz model after about 2 weeks, consistent with stable blood glucose levels during feeding and fasting periods.